Summary
Replication stress, a major cause of genome instability in cycling cells, is mainly prevented by the ATR-dependent replication stress response pathway in somatic cells. However, the replication stress response pathway in embryonic stem cells (ESCs) may be substantially different due to alterations in cell cycle phase length. The transcription factor MYBL2, which is implicated in cell cycle regulation, is expressed between hundred to thousand-fold more highly in ESCs compared to somatic cells. Here we show that MYBL2 functions to activate ATM and suppress replication stress in ESCs. Consequently, loss of MYBL2 or inhibition of ATM or Mre11 in ESCs, results in replication fork slowing, increased fork stalling and elevated origin firing. Additionally, we demonstrate that inhibition of CDC7 activity rescues replication stress induced by MYBL2 loss and ATM inhibition, suggesting that uncontrolled new origin firing may underlie the replication stress phenotype resulting from loss/inhibition of MYBL2 and ATM. Overall, this study proposes that in addition to ATR, a MYBL2-MRN-ATM replication stress response pathway functions in ESCs to control DNA replication initiation and prevent genome instability.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵5 Co-senior authors
This version of the manuscript has been revised to add more data to provide a more mechanistic insight between the relation of MYBL2 and ATM on the regulation of replication origin.